The myocardial injury that is detected when the heart is reperfused following surgically induced ischemic arrest may be due to pre-existing ischemia (occurring during the prearrest period and during the period of aortic cross clamping) or may be caused by the reperfusion process itself. We, and others, have shown that despite meticulous adherence to presently known principles of hypothermic cardioplegic arrest, reperfusion injury in a somewhat aborted form continues to occur and is probably related to the operative mortality that occurs subsequent to cardiac operations that have been performed in a technically acceptable manner. Recovery from ischemic arrest involved (1) the resumption of normal oxidative metabolism with the restoration of myocardial energy reserves; (2) reversal of ischemia induced changes such as cell swelling, ion distribution, intermediary metabolic, i.e. adenine nucleotide losses and finally, (3) repair of damaged organelles, i.e. mitochondria, sarcolemma and stabilization of metabolic pathways. We propose to focus on specific areas that have a high probability to yield promising avenues to ameliorate the reperfusion injury. Specifically, we plan to (1) investigate the effects of activated platelet obstruction in the microcirculation and to evaluate possible reversal by the use of new drug, 13-Azaprostonaic acid, a potent thromboxane A2 inhibitor; (2) provide nucleotide supplementation to rapidly increase high energy phosphate levels; (3) prevent and/or reverse myocardial rigor subsequent to intracellular calcium influx and (4) investigate chronically hypoxic hearts to determine whether they cope differently with reperfusion as compared to normally oxygenated hearts, particularly with regard to platelet microcirculatory trapping and intermediary metabolites and their restoration. It is hoped that these investigations will result in a pharmacologic strategy to prevent and/or reverse the "stone heart" phenomenon.